4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline, also known as imiquimod, is an immune response modifier, useful for treating genital warts. Imiquimod is also used for topical treatment of clinically typical nonhyperkeratotic, nonhypertrophic actinic keratoses on the face or scalp in immunocompetent adults and for the treatment of biopsy-confirmed, primary superficial basal cell carcinoma in immunocompetent adults, with a maximum tumor diameter of 2.0 cm, located on the trunk (excluding anogenital skin), neck, or extremities (excluding hands and feet). Imiquimod is marketed as a 5% cream under the trade name Aldara® and has the following structural formula (I):

The synthesis of imiquimod is described in U.S. Pat. Nos. 4,689,338 and 4,929,624 (to Minnesota Mining and Manufacturing Co. Inc.). The processes described therein involve an ammonolysis reaction carried out by heating the compound 4-chloro-1-isobutyl-1-imidazo[4,5-c]quinoline of formula (II) in the presence of ammonium hydroxide or ammonia in methanol under high pressure (e.g. in a steel bomb) at 150° C. to afford imiquimod of formula (I), as depicted in Scheme 1.

U.S. Pat. No. 4,988,815 describes a process for preparing imiquimod, which involves ammonolysis of the compound 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline.
Conventional processes using ammonolysis, e.g., as described in U.S. Pat. Nos. 4,689,338 and 4,929,624, are disadvantageous in that the reaction is conducted at high temperature and under pressure, which is undesirable with respect to industrial safety measures.
US Patent Application Publication No. 2005/0085500 discloses a process for preparing imiquimod in which 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline is converted to imiquimod in three steps. In the first step, 4-N-benzylamino)-1-isobutyl-1H-imidazo[4,5-c]quinoline is obtained by reacting 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline with large excess of benzylamine. In the second step, the acid addition salt of 4-(N-benzylamino)-1-isobutyl-1H-imidazo[4,5-c]quinoline is prepared, and in the third step imiquimod is obtained from the acid addition salt by reaction with NaOH. The above process is disadvantageous in that it is lengthy.
US Patent Application Publication No. 2006/0004202 discloses a process for preparing imiquimod in which 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline is converted to imiquimod by reaction with hydroxylamine in the presence of sodium acetate. However, imiquimod is obtained by this process in a relatively the low yield of 52%, which makes this process unattractive for industrial implementation.
International Patent Application Publication No. WO 2006/070379 discloses a process for preparing imiquimod in which 4-chloro-1-isobutyl-1H-imidazo-[4,5-c]quinoline is converted to 4-iodo-1-isobutyl-1H-imidazo[4,5-c]quinoline by reaction with sodium iodide in the acetone followed by converting the resulting 4-iodo-1-isobutyl-1H-imidazo[4,5-c]quinoline to imiquimod with methanolic ammonia at a temperature of 150-155° C. and high pressure. In this case, not only is the process lengthy (with the extra step of preparing the intermediate 4-iodo-1-isobutyl-1H-imidazo[4,5-c]quinoline) but also the reaction is conducted at high temperature and pressure.
Thus, there is a need for an improved process for preparing highly pure imiquimod starting from 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline, which is suitable for industrial use in comparison to conventional processes, and produces highly pure imiquimod in fewer steps and under more industrially viable conditions. The present invention provides such a process.